Many pharmacological active substances and also Levosimendan and/or its active metabolites OR-1896 and/or OR-1855 (which metabolites are also described in WO 2005/107756) are lipophilic, i.e., only sparingly or negligibly water soluble. The poor water-solubility of Levosimendan results in major difficulties in formulation, particularly when sterile and easily administrable homogenous aqueous solutions are needed. Therefore, the manufacture of Levosimendan solutions involves a number of problems which are caused by the sensitivity of Levosimendan against chemical and physical influences. For example Levosimendan in solutions is sensitive to a chemical degradation which limits the shelf life of solutions and may produce undesirable degradation products.
Levosimendan which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazi-nyl)phenyl]hydrazono]propanedinitrile, and methods for its preparation are described in EP 565546 B1 and WO 97/35841. Levosimendan is potent in the treatment of heart failure and has a significant calcium dependent binding to troponin. Levosimendan is a crystalline powder at room temperature and has a pKa of 6.26. At room temperature the solubility of Levosimendan in phosphate buffer is 0.4 mg/ml at a physiological pH of 7.4. At a pH value of 2 the solubility is as low as 0.02 mg/ml. Levosimendan is not stable in aqueous solutions at physiological pH and is subjected to hydrolytical decomposition. Therefore, Levosimendan is poorly soluble in water and precipitates easily from aqueous solutions. The precipitation of intravenous solutions is extremely dangerous because particulate material may occlude the blood vessels.
The current commercial formulation (Simdax®) (see also EP 1 210 085 B1) is based on the use of anhydrous ethanol and povidone (PVP) as solvents. And anhydrous citric acid is also used to obtain a concentration of 2.5 mg Levosimendan per ml at a pH of approximately 3. According to EP 1 210 085 B1 further solubility enhancing agents also include co-solvents such as propylenglycol, polyalkyleneglycols, e.g. polyethyleneglycol, poloxamers or polyvinylpyrrolidon and linoleic acid or glyceryl monolaurate.
In EP 1 210 085 B1 it was chosen to use an organic solvent approach for chemical stability reason at the pH of approximately 3. However, ethanol is a strong cellular poison and should be avoided in the treatment of humans for several reasons.
CN 1470238 A discloses water based Levosimendan preparations wherein the solubility of Levosimendan in water has been improved by the use of hydroxylpropyl-beta-cyclodextrin.
CN 1839842 A discloses pharmaceutical compositions containing Levosimendan and as solubility enhancing agent solutol HS15 (macrogol-15-hydroxystearate).
CN 1626085 A discloses a process for the preparation of pharmaceutical Levosimendan compositions wherein beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin or 3-hydroxypropyl-beta-cyclodextrin can be used as solubilizer.
CN 101411708 A discloses pharmaceutical compositions containing Levosimendan and hydroxpropyl-beta-cyclodextrin which serves as a solubilizing agent.
CN 1611220 A discloses preparations containing Levosimendan together citric acid, phosphor lipids and 2-hydroxypropyl-beta-cyclodextrin as solubilizing agents.
CN1689573 A discloses Levosimendan-beta-cyclodextrine preparations. Further ethanol and citric acid can be used to get parenteral solutions.
By applying an alternative solubilisation approach it is feasible to obtain a pharmaceutical formulation of Levosimendan at alternative pH values, also at physiological pH.
Levosimendan formulated as described above, i.e. using an organic solvent approach (anhydrous ethanol and/or PVP), can only be diluted with a 5% glucose solution and by using a predefined dilution procedure. Additionally, options for comedication with other drugs in the same i.v. system are very limited. By the present invention the disadvantages of intravenous administration of Levosimendan in ethanol and also the corresponding danger of precipitation when diluting the concentrate in infusion solutions are avoided. Furthermore the solution may advantageously be used at a physiological pH value and the solution may be diluted with different standard infusion solutions.